Chronic kidney disease (CKD) is a worldwide public health problem, with adverse outcomes of kidney failure, cardiovascular disease and premature death (Levey, 2005). Patients with CKD are at high risks for progression to the end stage renal disease and need the dialysis or kidney transplantation to maintain a long-term survival. Anemia, an early symptom of CKD, results from underproduction of endogenous erythropoietin (Epo) by kidney (Zarzecki et al., 2004). In addition to CKD, anemia is also associated with other diseases, such as cancer, acute and chronic infections, autoimmune, inflammation and chronic rejection after solid-organ transplantation (Weiss and Goodnough, 2005).
Epo is a glycoprotein hormone mainly produced in adult kidney and fetal liver. Epo exerts its effect by binding to erythropoietin receptor (Epo receptor) on cell surface. When cells sense a relatively low oxygen level (such as the hypoxia), Epo is produced and released to regulate proliferation, differentiation, maturation, and survival in erythroid lineage cells (Moritz et al., 1997 and Fisher, 2003). Abnormal Epo levels in bloodstream may be an indicator for bone marrow and renal diseases. Relatively low Epo levels have been seen in patients with CKD, primary polycythemia rubra vera and chemotherapy-induced anemia. Relatively high Epo levels have been seen in secondary polycythemia and renal cancer patients (Eckardt and Kurtz, 2005 and Hodges et al., 2007).
Besides being produced in kidney and liver tissues, Epo and its receptors have been found in non-erythroid tissues and organs, including brain, eye, heart, lung, gut, pancreas, muscle, uterus and gonads (Eckardt and Kurtz, 1992). Epo-Epo receptor signaling contributes to wound healing responses, angiogenesis and local tissue-protective functions, such as neuroprotections, cardiovascular protections and protections from tissue ischemia and ischemia/reperfusion injury (Paschos et al., 2008 and Arcasoy, 2008). It has been reported that Epo has renoprotective effects by reducing the extent of renal dysfunction and facilitating the recovery from cisplatin-induced acute renal failure (Sepodes et al., 2006 and Arcasoy, 2008).
Erythropoiesis-stimulating agents (ESAs) are recommended by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines to treat anemia of CKD in patients with treatment-responsive anemia. Recombinant human Epo (rHuEpo) has been approved for treating anemia of CKD, anemia in cancer patients receiving chemotherapy, for reducing transfusion requirements during surgery and for treating anemia in zidovudine-treated patients infected with the human immunodeficiency virus. A novel erythropoiesis stimulating protein (NESP), designed from Epo with a longer plasma half-life, has been approved for treating anemia in chronic renal failure (Fisher, 2003). It has been recommended that intravenous (i.v.) or subcutaneous (s.c.) administration of NESP be more than once per week for maintenance therapy. The pain, inconvenience due to frequent injection, and the development of anti-Epo antibodies because of inherent antigenicity associated with rHuEpo are of a great concerned (Bunn, 2007). Moreover, ESAs pose safety risks in patients with higher hemoglobin levels and may cause complications such as hypertension, thromboembolism, iron deficiency and severe pure red-cell aplasia (Wish and Coyne, 2007).
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies, especially in connection with erythropoiesis and kidney functions.